PRINCIPLES APPLYING TO THE PACKAGE INSERT

(PI)

Estelle Viljoen March 2013

Where to begin

• Re-read PI & PIL Guidelines• Check if there are any standardised text

for a specific class of medicine e.g ACE-inhibitors

• Check your main reference document whether it the latest possible version, and add from the latest editions of the reference any additional text

Where to begin cont.

• Use the acceptable references• Ensure that all copies are clear and

legible, also after copying• Enlarge small print references

Drafting the PI• Clearly distinguish between main headings and

subheadings e.g.

• PHARMACOLOGICAL ACTION

– Pharmacodynamics

– Pharmacokinetics

– Summary of Clinical Studies (where appropriate)

Drafting the PI (cont.)

• Transcribe the required data to your draft PI.• Cross-reference each statement to the

appropriate reference used and preferably indicate/mark the statement on the reference

• Use right-hand column to indicate reference/comment/motivation

• Number the pages & the lines of the PI

Trade name/INN

• When to use Trade name (TN) & when to use the INN

• Pharmacological action – INN• Indications to the end of the PI use the TN,

except for e.g. INN is secreted into breast milk, the concentration of INN is affected by another product

• The TN is used in the text in line with PN

When to use which reference for generic applications

• PHARMACOLOGICAL ACTION• Innovator PI, Goodman & Gilman• INDICATIONS• In line with the innovator• CONTRA-INDICATIONS• Innovator PI, Martindale, USP-DI

When to use which references

• WARNINGS• Innovator PI, Martindale, USP-DI• INTERACTIONS• Innovator PI, Martindale, USP-DI• PREGNANCY AND LACTATION• Innovator PI, Martindale, USP-DI

When to use which references

• DOSAGE AND DIRECTIONS FOR USE

• In line with the innovator PI• SIDE-EFFECTS AND SPECIAL

PRECAUTIONS• Innovator PI, Martindale, USP-DI

When to use which references

• KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT

• Innovator PI, Martindale, USP-DI

Headings of the PI

• SCHEDULING STATUSScheduling Status as determined and published by MCC on recommendation by the Scheduling Committee – requires a change to the legislation

• PROPRIETARY NAME AND DOSAGE FORM

Proprietary Name as approved by the Naming Committee

Headings of the PI (cont.)

• COMPOSITION– Active ingredient(s) and quantities– Inactive ingredients (list only)

• PHARMACOLOGICAL CLASSIFICATION– As determined by Regulation 25

Headings of the PI (cont.)• PHARMACOLOGICAL ACTION

– Pharmacodynamics

This section should start e.g.: “Abc is a recombinant

DNA-derived humanised monoclonal antibody”. Provide

information on the mechanism of action of the

molecule(s). Only information relevant to the Indications

may be included

Headings of the PI (cont.)• PHARMACOLOGICAL ACTION (continued)

– Pharmacokinetics

Provide information on Absorption, Distribution, Metabolism and

Elimination – and where appropriate on specific patient groups

such as age, renal impairment and hepatic insufficiency, (when

clinically relevant). Wherever possible it is advisable to have the

following subheadings: Absorption, Distribution, Metabolism and

Elimination and Special Populations

Headings of the PI (cont.)• PHARMACOLOGICAL ACTION (continued)

– Summary of Clinical Studies

This section will only be considered for inclusion if it is

deemed essential information for the professions to

make an informed decision, especially when important

to consider the safety:efficacy relationship

Headings of the PI (cont.)• INDICATIONS

– Self explanatory – for the MCC to accept or reject depending on the supporting information

• CONTRA-INDICATIONS– Absolute contra-indications e.g. hypersensitivity to

any of the ingredients, pregnancy, concomitant diseases, age, metabolic or immunological factors, prior adverse reactions to the medicine or class of medicines

Headings of the PI (cont.)• WARNINGS

– Relative contraindications should appear first, then warnings

– Specific safety issues, especially those that may lead to death or

serious harm and may be required to be placed in a prominently

displayed box and/or bolded font. Such information may be

displayed at the top of this section, or may be displayed

elsewhere in the package insert, where deemed appropriate

Headings of the PI (cont.)• INTERACTIONS

– Information on clinically relevant interactions based on the pharmacodynamics and/or pharmacokinetics

– The order of presentation should be contraindicated combinations, those where concomitant use is not recommended, followed by others

– Give detail of the mechanism of the interaction– Interactions referred to in other sections of the package

insert should be outlined and cross-referenced to the other sections

– Absence of an interaction - only if likely to have clinical interest

– Interactions with laboratory tests

Headings of the PI (cont.)• PREGNANCY AND LACTATIONPregnancy

– Possible scenarios: Pregnancy as a CI, add information from human or experimental studies, if appropriate.

– Inadequate information available– The statement generally used when no information is

available: “Safety in pregnancy and lactation has not been established”

Headings of the PI (cont.)

• PREGNANCY AND LACTATION–Women of Childbearing Potential

- Information on pregnancy testing, - Use of contraception - Any period during which contraception should be

avoided

Headings of the PI (cont.)

• PREGNANCY AND LACTATION

–Lactation

- Excreted in breast milk, mothers should not breast-

feed their babies

Headings of the PI (cont.)• DOSAGE AND DIRECTIONS FOR USE

– route of administration for each indication – dose and dose interval, duration of treatment where

relevant – maximum recommended single, daily and/or total

dose– dosage adjustment for age, renal insufficiency, liver

disease, where applicable – monitoring advice, where applicable

Headings of the PI (cont.)

• DOSAGE AND DIRECTIONS FOR USE

- Directions for use

- Handling instructions

- Incompatibilities

Headings of the PI (cont.)• SIDE-EFFECTS AND SPECIAL

PRECAUTIONS Side-Effects

– Information on all adverse reactions from clinical trials, post-marketing studies or spontaneous reports attributed to the medicine

– Clinical trials/studies and post-marketing data should be presented separately

– Classification of adverse reactions according to a system organ class (SOC) -MedDRA or WHOART

Headings of the PI (cont.)

Side-Effects (cont.)

– Frequency reporting of Side-effects for NCEs:• Clinical trial data: adverse reactions should be ranked

according to the CIOMS convention i.e.: Very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥1/1 000, <1/100); rare (≥ 1/10 000, < 1/1000); very rare (≤ 1/ 10 000), including isolated reports, not known (cannot be estimated from available data).

• For data from sources other than clinical trial data: When the frequency of occurrence is not available from clinical studies, the terms “frequent” or “less frequent” may be used

Headings of the PI (cont.)

Side Effects (cont.)

• For post-marketing data and spontaneous report: No frequency

categories can be allocated to reports from a spontaneous

reporting system.

• Post-marketing studies: Information from post-marketing studies

(e.g. phase IV studies) should be separate from that obtained

from pre-marketing clinical trials, with frequency categories

according to the CIOMS

Headings of the PI (cont.)Side-effects (cont.)

– Frequency reporting of Side-effects for MSM applications:• The frequency of occurrence should be reflected as

“Frequent” or “Less frequent” or “Frequency not known”.• Frequent = very common (≥ 1/10); common (≥ 1/100, < 1/10) • Less frequent = uncommon (≥1/1 000, <1/100); rare (≥ 1/10

000, < 1/1000); very rare (≤ 1/ 10 000), including isolated reports

• Frequency not known = frequency cannot be estimated from available data and posts-marketing data.

Headings of the PI (cont.)Side-effects (cont.) - If there are only a few adverse reactions in total,

classification by SOC may be unnecessary

– Any adverse reaction resulting directly from an interaction should be included and cross-referenced to Interactions

– Adverse reactions which apply to the therapeutic, chemical or pharmacological class, which may not have been observed yet in relation to the product, but which are generally accepted as being attributable to other compounds in the class. The fact that this is a class attribution should be mentioned

Headings of the PI (cont.)Side-effects (cont) - Any adverse reaction warnings necessary for

excipients or residues from the manufacturing

process should be included

– In case of combination products, where it is known

which particular adverse reactions are attributable to

which component, the information should be

presented separately

Headings of the PI (cont.)

Special Precautions

- Measures to be taken to avoid specific adverse

reactions should be mentioned here

- Any warnings/precautions necessary

relating to excipients

Headings of the PI (cont.)

Effects on ability to drive and use machines

Specify whether the medicine has - no or negligible influence

- minor or moderate influence - major influence on these

abilities

Headings of the PI (cont.)• KNOWN SYMPTOMS OF OVERDOSAGE

AND PARTICULARS OF ITS TREATMENT– Acute symptoms and signs and potential sequelae of

overdosage

– Recommended management of overdose e.g.

symptomatic treatment, or in relation to specific

agonists/antagonists or methods to increase

elimination of the medicine e.g. dialysis.

Headings of the PI (cont.)

• Identification– In line with the registration dossier

• Presentation– In line with the registration dossier

• Storage Instructions– In line with the registration dossier

Headings of the PI (cont.)

• Registration Number

– Allocated only following registration. During the pre-

registration phase it remains an application number• Name and Business Address of the Holder of the

Certificate of Registration

• Date of Publication of the Package Insert– Date of registration followed by most recently revised

MCC approved PI

Basic Principles

• Ensure that all copies are legible• Ensure copies of all references are

included in the submission• Mark package inserts clearly i.e.

Response to Clinical Committee Recommendation - Proposed Package Insert

• Date all package inserts

Basic Principles

• Check the PI & PIL for spelling and grammar

• Ensure all abbreviations are written out the first time it is used in the text

• Preferably have a peer-review process• Provide some detail relevant to the

application in the covering letter

Basic Principles

• The following apply to updating of PIs as well as responses to recommendations

• Underline all new inclusions• [Square bracket and strike-through] all

intended deletions• [Dotted underlining for rewording] of a

statement/section

Editorial Matters

• Use British English• Drug = Medicine• Physician = Medical practitioner/doctor• Use decimal comma• Spaces between numerical values and

units (also apply to %)• SI Units = e.g. mmol/l & µmol/litre• ℓ vs. l

Terminology• Cockroft and Gault formula for renal impairment in adults• Clcr (mℓ/minute)

• For males: •     = [140 – age] x Wt (kg)  •                  Scr (µmol/ℓ) •  • For females:•      = [140 – age] x Wt (kg) x 0,85  •                   Scr (µmol/ℓ)  

Terminology

• Breast-feeding vs. breast feeding vs. breastfeeding

• Hypokalaemia vs. hypokalemia• Neutropenia vs. neutropaenia• Cyclosporine vs. ciclosporin• Lignocaine vs. lidocaine• Dysrhythmia vs. arrhythmia

The end